Clinical trials for cell therapy reveal only modest benefits on cardiac function in heart failure (HF) patients ? leaving the future of this therapeutic modality uncertain. Despite years of research on the topic, the cell therapy field remains engrossed in controversies regarding the mechanism(s) of action of donor cells and the cell type best suited to promote cardiac repair. Two competing hypotheses have been forwarded to explain the mechanisms underlying cell therapy-mediated cardiac repair, namely donor cell direct differentiation (contributing to new cardiac parenchyma) and paracrine signaling (promotion of endogenous repair mechanisms through cytokine and/or extracellular vesicle (EV) secretion). Given that donor cell populations exhibit poor rates of retention and limited long-term persistence after delivery in HF models, paracrine signaling is viewed as a major mechanism of cell-mediated cardiac repair. However, there is also evidence implicating a link between therapeutic efficacy and donor cell cardiovascular fate decisions; although the mechanisms remain unknown. It is known that different cell types possess distinct trophic factor secretion profiles and paracrine signaling activities. Thus, we posit that cardiovascular cell lineage commitment-dependent variations in paracrine signaling are likely to have a significant impact on donor cell reparative capacity in cell-mediated cardiac repair. Further, as EVs have been identified as important mediators of progenitor cell-induced cardiac regeneration, we hypothesize that donor cell cardiomyogenic lineage commitment regulates the expression and synthesis of EV-resident cardiotrophic factors, which mediate cardiac repair. To test this hypothesis, we will use genetic and pharmacologic approaches for enhancing cardiogenic factor expression to assess the effects of cardiomyogenic lineage commitment on the reparative capacity of cardiac mesenchymal cells (CMCs) and lineage-dependent adaptations in CMC EV signaling. Aim 1 will interrogate the impact of genetic- and pharmacologic-mediated induction of cardiogenic factor expression on CMC cardiovascular lineage commitment and EV paracrine signaling. Aim 2 will assess the effect of cardiomyogenic lineage commitment on the reparative capacity of CMCs following administration in a chronic infarct model. Aim 3 will evaluate the consequences of EV administration, derived from nave and cardiomyogenic lineage-committed CMCs, on cardiac repair. The results of this project will establish an unidentified link between progenitor cell cardiovascular lineage commitment and modifications in EV secretion/paracrine signaling, as well as elucidate novel targets and pathways that may be exploited to enhance the efficacy of cell therapy.